Because sex differences exist in almost all aspects of the metabolic syndrome, treatments developed using only male subjects elicit a disproportionate risk for adverse, off-target, or simply ineffective outcomes among female patients. Yet the vast majority of pre-clinical biomedical research focuses only on males. Fibro- blast growth factor 21 (FGF21), a polypeptide hormone produced by the liver in response to nutritional stress, is a promising target for treatment of metabolic disease. In males, administration at pharmacologic doses im- proves glucose tolerance, and reduces body weight and body fat by increasing sympathetic outflow to adipose tissue, increasing thermogenesis. Consequently, several major companies are developing FGF21-based com- pounds for clinical use. Yet surprisingly little is known about the metabolic actions of FGF21 in females. Our recently published and preliminary data strongly support that FGF21 functions as a key mechanism facilitating the sexually dimorphic metabolic response to dietary protein ?dilution??a novel nutritional intervention eliciting weight loss and improved glucose and lipid metabolism in male mice, rats and humans. In this project, we plan to address the next critical step, by identifying specific neuroendocrine and cell-autonomous mechanisms by which FGF21 elicits divergent metabolic responses in males and females. The overarching hypothesis in this proposal is that, in the presence of estrogen receptor-beta, FGF21 signaling in the hypothalamus increases the sympathetic drive to adipose tissue in males but not females, and FGF21 signaling in the adipocyte inhibits the catabolic response to adrenergic stimulation in females but not males. We will test hypothesis using pharmaco- logic, genetic and nutritional manipulations of FGF21 signaling in the brain (Aim 1) and adipose tissue (Aim 2) of male and female mice, together with indirect calorimetry, and isotopic tracer-assisted measurements of lipid turnover. These experiments are expected to delineate neuroendocrine and molecular mechanisms contrib- uting to the sexually dimorphic regulation of fat mass, thereby facilitating the appropriate and targeted delivery of nutritional and pharmacological interventions in obesity and metabolic disease. In light of the considerable interest in FGF21 itself as a therapeutic target, we are surprised to note that almost nothing is known about its metabolic effects in female subjects. Therefore, this work is not only physiologically important, but it will also provide new insights in the clinical application of FGF21-based therapeutics in both men and women.